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An opioid antagonist that is selective for peripheral opioid receptors would be useful to treat two of the most common adverse effects of opioids: opioid bowel dysfunction and pruritus. Although constipation may be treated with the use of bowel

IV PC A: Must be programmed. IONSYS™ (fentanyl HCI): delivery through IV line Preprogrammed and needle free

IV PC A: Must be programmed. IONSYS™ (fentanyl HCI): delivery through IV line Preprogrammed and needle free

IV PCA = Intravenous pa (lent-controlled analgesia.

Figure 111-63. Compared to PCA the needle free Ionsys® system in situ, placed on the upper arm. By pushing a button, fentanyl iontophoretically is driven through the skin where it migrates into the capillaries

IV PCA = Intravenous pa (lent-controlled analgesia.

Figure 111-63. Compared to PCA the needle free Ionsys® system in situ, placed on the upper arm. By pushing a button, fentanyl iontophoretically is driven through the skin where it migrates into the capillaries regimens and pruritis with antihistamines, these agents are sometimes ineffective, are themselves associated with adverse effects, and often require the use of multiple agents. A recent comprehensive review examined available data for opioid antagonists, and concluded that peripherally acting agent's show the greatest promise because of their ability to reverse opioid-induced constipation and pruritus without compromising centrally mediated pain control. A potential advantage of opioid antagonists is the use of a single agent for the treatment of multiple adverse effects, which offers advantages of decreased drug costs and nursing time, improved drug compliance, and ease of administration [199]. Postoperative ileus, a serious side effect of opioid therapy, occurs commonly in patients undergoing lower abdominal surgery. Inhibition of gut motility occurs through activation of peripheral ^-opioid receptors in the gastrointestinal tract. Available opioid antagonists (e.g., naloxone) are not useful clinically to prevent this effect because they are readily absorbed, cross the blood-brain barrier, and act centrally to reverse analgesia.

Alvimopan (Adolor Corporation; Figure III-64) is a recently developed opioid antagonist that, like methylnaltrexone, has pharmacologic activity restricted to peripheral opioid receptors, and has shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia [200]. Alvimopan, being a moderately large, polar molecule, does not cross the blood-brain barrier [201].

Alvimopan may prove useful clinically as a selective inhibitor of gastrointestinal opioid receptors, thereby decreasing the incidence of postoperative ileus [202]. In normal volunteers, the prolongation of gastrointestinal transit time observed after administration of i.v. morphine (0.05 mg/kg) was prevented by oral administration of Alvimopan (4 mg). While morphine prolonged gastrointestinal transit time from 69±33 to 103±37min (p = 0.005), this was prevented by Alvimopan (p = 0.004; Figure III-65).

Figure 111-64. Molecular structure of the selective peripheral opioid antagonist Alvimopan. Being a piperdine derivative with high affinity to the opioid ^-receptor, due to its large molecular size, cannot cross the blood-brain barrier

Figure 111-64. Molecular structure of the selective peripheral opioid antagonist Alvimopan. Being a piperdine derivative with high affinity to the opioid ^-receptor, due to its large molecular size, cannot cross the blood-brain barrier

A randomized, controlled study of 78 patients who underwent lower abdominal surgery (15 patients, partial colectomy; 63 patients, total hysterectomy) evaluated its effect on recovery of gastrointestinal function. Patients received one capsule containing 1 mg or 6 mg of Alvimopan or an identical-appearing placebo 2 h before surgery and then twice daily until the first bowel movement or until hospital discharge. All patients received opioids for postoperative analgesia. Compared to the control group, the group that received 6 mg Alvimopan experienced significantly faster median times to passage of first flatus (49 h versus 70 h; p = 0.03), first bowel movement (70 h versus 111 h; p = 0.01), and time to discharge (68 h versus 91 h; p = 0.03) [203]. In addition to the reversal of constipation alvimopan was also able to reduce the incidence of postoperative nausea and vomiting (PONV) in patients having received an opioid for postoperative pain (Figure III-66).

Figure 111-65. Prevention of morphine-induced delay in oral-cecal transit times, using the lactulose hydrogen breath test (Adapted from [201])
Pharmacological Effects Morphine
Figure 111-66. Reduction of PONV in patients after hysterectomy and colectomy with the peripheral opioid antagonist alvimopan (Adapted from [204])

Another compound, which may be of interest to anesthesiologists and pain specialists and recently was approved by the FDA, is methylnaltrexone (Progenics Pharmaceuticals). Methylnaltrexone is the quaternary derivative of the opioid antagonist naltrexone [205].

It was originally developed by Leon Goldberg for use in cancer patients with opiate-induced constipation (Figure III-67), and now is indicated in all patients receiving opioids for acute and chronic pain.

In a subsequent randomized, double-blind, placebo-controlled study in human volunteers, single oral doses of methylnaltrexone (ranging from 0.64 to 19.2 mg/kg) acted quite similarly. Oral methylnaltrexone prevented the morphine-induced delay in oral-cecal transit time in a dose dependent manner without affecting analgesia

Pharmacological Effects Morphine
Figure III-67. Molecular structure of opioid antagonist naltrexone (left) and its derivative methylnaltrexone (right), a selective peripheral antagonist, which is not able to cross the blood-brain barrier
Figure III-68. Dose-related response with and without methylnaltrexone (MNTX 0.7, 2.1, 6,4 and 19.2mg/kg respectively) on oral-cecal transit time in volunteers after morphine 0.05mg/kg when normalized to control (= 100) (Adapted from [206])

(Figure III-68). Pharmacokinetic data revealed the effects primarily in the gut itself, not in response to systemic absorption of the drug [206]

Although the acute effects of opiates on GI motility proved to be completely reversible by methylnaltrexone, the efficacy of methylnaltrexone as a therapy in opiate-tolerant individuals represented a more complex problem of dose titration. To resolve this problem, a double-blind, placebo-controlled, randomized clinical trial was performed in 22 subjects undergoing chronic methadone maintenance therapy for addiction [207]. Normally, patients on methadone maintenance programs laxate only infrequently, sometimes only once or twice per week, and have a marked reduction in oral-cecal transit. Subjects in the study received methylnaltrexone intravenously on an ascending dose schedule. Both oral-cecal transit time and laxation were recorded and signs of withdrawal were monitored. Although oral-cecal transit time was normalized with methylnaltrexone, no subject showed psychological or physical signs of opiate withdrawal. In the 11 subjects in the placebo-treated group laxation response was not affected, whereas 10 of the 11 subjects in the methylnaltrexone-treated group evacuated on day 1, and all 11 evacuated on day 2.

In preliminary human studies, administration of small doses of morphine (averaging 3-5 mg) to volunteers slowed GI transit (as measured by oral-cecal transit time) by 50%. When subjects were treated with small doses of methylnaltrexone (0.4 mg/kg intravenously) this opiate-induced change in motility was almost completely reversed. Importantly, the cold pressor test demonstrated that morphine analgesia was intact with methylnaltrexone. This represented the first demonstration of separation of the central and peripheral effects of opiates on GI motility in humans [208]. Laxation occurred within 1 min of injection of the drug. The GI

motility of methadone maintenance patients was exquisitely sensitive to methylnal-trexone (5 times more sensitive in the chronic opiate users than in the volunteers). Goldberg reasoned that a charged molecule with opiate antagonist properties would not penetrate the blood-brain barrier, thus preserving central analgesia when given with opiates. In the in vitro studies of human and guinea pig gut, methylnaltrexone had one-third the potency of naloxone in reversing morphine-induced inhibition of contraction. In these studies, 97% of morphine's effect on gastric motility could be reversed by methylnaltrexone and the effect was luminal. Similar effects were noted with oral methylnaltrexone in 12 methadone maintenance subjects. In another study, oral methylnaltrexone reversed hypomotility and bowel movement in 5 h at the highest dose (Figure III-68). The route of administration may be significant. Laxation occurred immediately after IV administration of methylnaltrexone but several hours after oral administration. After subcutaneous administration, changes in oral cecal transit time occurred over a period of about 15min [205]. Thus, the several routes for administration, oral, intravenous, or subcutaneous, have various onset and duration times.

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Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

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